Psychiatric disorders are heterogeneous and of multifactorial origin.1 The illness course is often chronic and associated with high rates of nonrecovery, episode recurrence, interepisodic dysfunction, and morbidity as well as premature mortality.

It is therefore not surprising that MDD, bipolar disorder, and schizophrenia are among the primary leading causes of disability and economic burden worldwide. One major contributor to the economic burden associated with these conditions is the limited capability of available treatment options to effectively modify the disease process, fully restore function, halt illness progression, and treat cognitive deficits.

Since the original description of lithium’s efficacy for mania in 1948, followed by chlorpromazine and iproniazid shortly thereafter, no substantial pharmacological advances have been made in the field of psychiatry. Although advances in safety, tolerability, and simplicity of use have been made, the long-term outcomes for most patients with MDD, bipolar disorder, or schizophrenia remain largely the same as they did several decades ago, ie, many of these patients do not achieve symptomatic, syndromal, and functional recovery with conventional pharmacotherapy. This underscores the need for restructuring the current disease model.

The prevailing theory for the past 50 years has been that affective and psychotic disorders are subserved by disturbances in monoamines. Yet, despite intensified research efforts, monoamines have not proved to be reliable biomarkers of psychiatric disorders and no disease-modifying agents have been discovered on the basis of this model. A more comprehensive disease model that encompasses other physiological systems may accelerate progress toward novel treatment development.

Results from preclinical and clinical translational research indicate that disturbances in inflammation may play a role in the pathophysiology of psychiatric disorders, including MDD, bipolar disorder, and schizophrenia. Hence, it could be hypothesized that inflammatory mediators may constitute novel targets for drug development.

Cytokines

Cytokines are pleiotropic and often redundant soluble proteins that regulate survival, differentiation, proliferation, and effector functions of tissues and cells. While these proteins are well-known mediators of innate and adaptive immunity, more recently they have been implicated in a variety of other systems. For example, inflammatory cytokines have been shown to interact with neurotransmitter metabolism, neuroendocrine function, and neural as well as glial plasticity. Peripherally and centrally derived inflammatory cytokines exert a bidirectional influence across the blood-brain barrier or via peripheral afferent nerve fibers (ie, vagus nerve).1,2

Inflammatory comorbidity

The increased incidence of inflammatory diseases in individuals with psychiatric disorders (eg, cardiovascular disease, obesity, autoimmune diseases) provides conjectural evidence that inflammatory mediators may be involved in the pathophysiology of these conditions. The obverse association is also reported, wherein in individuals with rheumatic diseases, the incidence of subsequent psychiatric disorders is higher.

In a population-based study that evaluated the entire Swedish population, the standardized incidence ratio of subsequent psychiatric disorders was highest for individuals with systemic lupus erythematosus followed by ankylosing spondylitis and rheumatoid arthritis.3 Further analysis revealed a higher incidence of subsequent affective, psychotic, and personality disorders, as well as dementia and delirium, although the risk of psychotic disorders was significant only in women with rheumatoid arthritis and systemic lupus erythematosus.

Other population-based studies, however, have reported a lower incidence of schizophrenia in individuals with rheumatoid arthritis.4,5

Higher rates of depression are also evident with various other medical conditions, including obesity and cardiovascular disease.1 The bidirectional co-occurrence of psychiatric and autoimmune or inflammatory diseases suggests the involvement of common networks central to the pathophysiology of these conditions.